Project 1: PRINT Nanoparticles: Calibration Quality Nano-tools for Studying the Effect of Particle Attributes on Biodistribution, Clearance and Optimized Delivery of Therapeutics Nanoparticle (NP) drug delivery systems can preferentially deliver and release a therapeutic cargo in the optimal dosage range at the site of disease, which in turn has the potential to result in improved therapeutic efficacy, reduced side effects and improved patient compliance. In fact, some of these improvements have already been realized in first generation nanotechnology-based therapeutics, including Doxil and Abraxane. Current research is now focused on engineering the next generation of nanoparticle therapeutics. Challenges in successful design are the numerous biological barriers that impede efficacious and efficient delivery of drugs to the site of the disease upon systemic administration. A thorough understanding of the impact of the physical parameters of the particlessize, shape, surface characteristics and deformability on biodistribution will aid in the rational design of nanoparticle therapeutics. Particle Replication In Nonwetting Templates is a novel method for the molding of shape-specific particles at the nanometer scale developed by DeSimone and coworkers at the University of North Carolina at Chapel Hill. PRINT offers an unprecedented opportunity to study the problems associated with nanoparticle delivery and, more importanfiy, offers a versafile platform to engineer solutions to these problems. In this project, we will exploit the advantages of PRINT to generate calibration quality nano-tools to define the geometric (size, shape), surface (zeta potential, stealthing ligands) and deformability limitations associated with the delivery of drugs using different dosage forms (IV and IP) (Aim 1). In addifion, we will use PRINT particles as a platform to test biomimetic strategies for the evasion of clearance by the mononuclear phagocytic system (MPS) (Aim 2). Finally, we will use the versatility of PRINT to address the role of particle characteristics on site specific targeting and controlled release of drugs in the tumor bed to improve therapeutic index (Aim 3).